tsRNA-10105-enriched Migrasomes Mediate Hepatocellular Carcinoma Immunosuppressive Microenvironment by Inducing M2 Macrophage Polarization.

Abstract

Hepatocellular carcinoma (HCC) is characterized by a complex immunosuppressive microenvironment, which significantly influence tumor progression. Migrasomes, newly identified extracellular vesicles, have emerged as a novel mode of intercellular communication. However, their roles in HCC immune microenvironment are rarely studied. Here, we observed the migrasome markers and M2 polarization levels in HCC patient tissues using immunofluorescence. Migrasomes were isolated from HCC cells and characterized using electron microscopy, immunofluorescence, and Western blot. The effects of migrasomes on macrophage polarization and HCC progression were investigated in vitro and in vivo. Small RNA-seq was conducted to screen for key tsRNA. We discovered that the levels of the migrasome marker and M2 macrophage marker were elevated in liver tumor tissues. Migrasomes derived from HepG2 induced macrophage M2 polarization, as indicated by the increased expression of M2 polarization marker, and the suppressed expression of M1 polarization marker. Macrophages treated with these migrasomes further stimulated the proliferation, migration, and invasion of malignant cells in vitro and augmented tumor growth and metastasis in vivo. Compared to the healthy individuals, the sera of HCC patients demonstrated elevated expression of tsRNA-10105 in migrasomes. Inhibition of tsRNA-10105 significantly abolished the inducing effect of cancer cell migrasomes on the M2 macrophages polarization. Our findings indicate that migrasome-derived tsRNA-10105 from HCC cells can induce the M2 macrophages polarization, which in turn augments survival and migration of HCC cells. This work provides insights into the mechanisms of the immunosuppressive microenvironment in HCC and offers novel perspectives for the immunotherapy of liver cancer.